The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.

https://cdr.lib.unc.edu/downloads/v692t8920

A global reference for human genetic variation.

Objective To determine the effects of antiplatelet therapy among patients at high risk of occlusive vascular events. Design Collaborative meta-analyses (systematic overviews). Inclusion criteria Randomised trials of an antiplatelet regimen versus control or of one antiplatelet regimen versus another in high risk patients (with acute or previous vascular disease or some other predisposing condition) from which results were available before September 1997. Trials had to use a method of randomisation that precluded prior knowledge of the next treatment to be allocated and comparisons had to be unconfounded-that is, have study groups that differed only in terms of antiplatelet regimen. Studies reviewed 287 studies involving 135 000 patients in comparisons of antiplatelet therapy versus control and 77 000 in comparisons of different antiplatelet regimens. Main outcome measure "Serious vascular event": non-fatal myocardial infarction, non-fatal stroke, or vascular death. Results Overall, among these High risk patients, allocation to antiplatelet therapy reduced the combined outcome of any serious vascular event by about one quarter; non-fatal myocardial infarction was reduced by one third, non-fatal stroke by one quarter, and vascular mortality by one sixth (with no apparent adverse effect on other deaths). Absolute reductions in the risk of having a serious vascular event were 36 (SE 5) per 1000 treated for two years among patients with previous myocardial infarction; 38 (5) per 1000 patients treated for one month among patients with acute myocardial infarction; 36 (6) per 1000 treated for two years among those with previous stroke or transient ischaemic attack; 9 (3) per 1000 treated for three weeks among those with acute stroke; and 22 (3) per 1000 treated for two years among other high risk patients (with separately significant results for those with stable angina (P=0.0005), peripheral arterial disease (P=0.004), and atrial fibrillation (P=0.01)). In each of these high risk categories, the absolute benefits substantially outweighed the absolute risks of major extracranial bleeding. Aspirin was the most widely studied antiplatelet drug, with doses of 75-150 mg daily at least as effective as higher daily doses. The effects of doses lower than 75 mg daily were less certain. Clopidogrel reduced serious vascular events by 10% (4%) compared with aspirin, which was similar to the 12% (7%) reduction observed with its analogue ticlopidine. Addition of dipyridamole to aspirin produced no significant further reduction in vascular events compared with aspirin alone. Among patients at high risk of immediate coronary occlusion, short term addition of an intravenous glycoprotein IIb/IIIa antagonist to aspirin prevented a further 20 (4) vascular events per 1000 (P <0.0001) but caused 23 major (but rarely fatal) extracranial bleeds per 1000. Conclusions Aspirin (or another oral antiplatelet drug) is protective in most types of patient at increased risk of occlusive vascular events, including those with an acute myocardial infarction or ischaemic stroke, unstable or stable angina, previous myocardial infarction, stroke or cerebral ischaemia, peripheral arterial disease, or atrial fibrillation, Low dose aspirin (75-150 mg daily) is an effective antiplatelet regimen for long term use, but in acute settings an initial loading dose of at least 150 mg aspirin may be required. Adding a second antiplatelet drug to aspirin may produce additional benefits in some clinical circumstances, but more research into this strategy is needed.

/pdf/collaborative-meta-analysis-of-randomised-trials-of-8dyu3duelv.pdf

Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients

Background Retinal ischemia induces intraocular neovascularization, which often leads to glaucoma, vitreous hemorrhage, and retinal detachment, presumably by stimulating the release of angiogenic molecules. Vascular endothelial growth factor (VEGF) is an endothelial-cell-specific angiogenic factor whose production is increased by hypoxia. Methods We measured the concentration of VEGF in 210 specimens of ocular fluid obtained from 164 patients undergoing intraocular surgery, using both radioimmunoassays and radioreceptor assays. Vitreous proliferative potential was measured with in vitro assays of the growth of retinal endothelial cells and with VEGF-neutralizing antibody. Results VEGF was detected in 69 of 136 ocular-fluid samples from patients with diabetic retinopathy, 29 of 38 samples from patients with neovascularization of the iris, and 3 of 4 samples from patients with ischemic occlusion of the central retinal vein, as compared with 2 of 31 samples from patients with no neovascular disorders (P<0.00...

https://www.nejm.org/doi/pdf/10.1056/NEJM199412013312203

Vascular Endothelial Growth Factor in Ocular Fluid of Patients with Diabetic Retinopathy and Other Retinal Disorders

A global reference for human genetic variation

Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.

Data gathered on the number of physicians and health care costs in the United States over a 30-year period from 1970 through 1999 were correlated and analyzed using bivariate linear regression. The rise in the number of practicing physicians theoretically predicts 96 percent of the variability in rise of total U.S. health expenditures, 96 percent of the variability in rise of physician service expenditures, 98 percent of the variability in rise of hospital service expenditures, and 86 percent of the variability in rise of prescription pharmaceutical expenditures. If the rate of growth in the number of physicians continues unchanged in the current fee-for-service climate, the model herein predicts that the growth in health care costs will likely continue to rise substantially faster than the rate of growth of the U.S. population and the rate of inflation. The addition of nonphysician providers with the same clinical privileges will likely exacerbate the situation of rapidly escalating medical costs. It is also possible that the excess number of physicians and other health care providers with the same clinical privileges as physicians may decrease the overall quality of health care. Reducing the rise in the number of physicians and nonphysician practitioners may help to decrease overall health care expenditures and improve overall quality of health care in the United States.

Physician manpower and health care expenditures in the United States: a thirty-year perspective.

Objective To perform a base case, comparative effectiveness, and cost-effectiveness (cost-utility) analysis of penetrating keratoplasty for patients with severe keratoconus. Methods Visual acuity data were obtained from a large, retrospective multicenter study in which patients with keratoconus with less than 20/40 best corrected visual acuity and/or the inability to wear contact lenses underwent penetrating keratoplasty, with an average follow-up of 2.1 years. The results were combined with other retrospective studies investigating complication rates of penetrating keratoplasty. The data were then incorporated into a cost-utility model using patient preference-based, time trade-off utilities, computer-based decision analysis, and a net present value model to account for the time value of outcomes and money. The comparative effectiveness of the intervention is expressed in quality-of-life gain and QALYs (quality-adjusted life-years), and the cost-effectiveness results are expressed in the outcome of $/QALY (dollars spent per QALY). Results Penetrating keratoplasty in 1 eye for patients with severe keratoconus results in a comparative effectiveness (value gain) of 16.5% improvement in quality of life every day over the 44-year life expectancy of the average patient with severe keratoconus. Discounting the total value gain of 5.36 QALYs at a 3% annual discount rate yields 3.05 QALYs gained. The incremental cost for penetrating keratoplasty, including all complications, is $5934 ($5913 discounted at 3% per year). Thus, the incremental cost-utility (discounted at 3% annually) for this intervention is $5913/3.05 QALYs = $1942/QALY. If both eyes undergo corneal transplant, the total discounted value gain is 30% and the overall cost-utility is $2003. Surgery on the second eye confers a total discounted value gain of 2.5 QALYs, yielding a quality-of-life gain of 11.6% and a discounted cost-utility of $2238/QALY. Conclusions Penetrating keratoplasty for patients with severe keratoconus seems to be a comparatively effective and cost-effective procedure when compared with other interventions across different medical specialties.

The value-based medicine comparative effectiveness and cost-effectiveness of penetrating keratoplasty for keratoconus.

Treatment of foveal pigment epithelial detachments with contiguous extrafoveal choroidal neovascular membranes.

Thirteen patients with BB-gun injuries to the eye are reported. Included are nine instances of double perforation, one case of vitreous hemorrhage, a case of late rhegmatogenous retinal detachment, one of retinitis sclopetaria, and a case of an intraocular shell casing introduced indirectly via an inadvertant BB-gun discharge into a drawer of bullets. Among the nine globes with double perforation, seven eyes were irreparably damaged and eventually enucleated, while two remained with hand motions vision. Despite modern vitrectomy techniques, double perforating BB-gun injuries to the globe imply a grim prognosis.

BB-gun injuries to the eye

AIM—To determine the accuracy of visible retinal emboli as a diagnostic "test" for the likelihood of receiving anticoagulation or cardiac surgery based on the results of transthoracic echocardiography, in the setting of acute retinal arterial occlusion.
METHODS—A multicentre retrospective diagnostic study at Kingston Eye Centre, Queen's University, Kingston, Ontario; Wills Eye Hospital, Philadelphia; Ottawa Eye Institute, Ottawa, Ontario; and the Halifax Infirmary, Halifax, Nova Scotia of 104 patients with both embolic and non-embolic acute retinal arterial obstruction who underwent transthoracic echocardiography was performed, to determine the accuracy of visible retinal emboli as a diagnostic "test" for anticoagulation or cardiac surgery. Anticoagulation or surgical intervention on the basis of abnormalities was detected solely through the technology of transthoracic echocardiography.
RESULTS—41 patients had visible retinal emboli (calcific, cholesterol, or fibrin). The remaining 63 had no evidence of embolic disease. The sensitivity of emboli for the likelihood of a patient receiving anticoagulation or cardiac surgery was 50%. The specificity, positive predictive value, and negative predictive value were 62%, 15%, and 90%, respectively. The likelihood ratio (LR=1.31) obtained given the presence of a visible retinal embolus was neither clinically nor statistically significant (LR+ve = 1.31; 95% CI (0.91, 3.16)). This likelihood ratio, when applied to a patient with a pretest probability of 50%, results in a post-test probability of 56.7%.
CONCLUSIONS—These results demonstrate that the presence of a visible retinal embolus should not be the sole determinant of whether to order transthoracic echocardiography, as the likelihood ratio for a patient receiving anticoagulation or cardiac surgery, given the presence of a visible retinal embolus was only 1.31.

Keywords: retinal emboli; cardioembolic lesions; anticoagulation; cardiac surgery

https://bjo.bmj.com/content/bjophthalmol/82/6/655.full.pdf

Gary C. Brown

Papers

Physician manpower and health care expenditures in the United States: a thirty-year perspective.

The value-based medicine comparative effectiveness and cost-effectiveness of penetrating keratoplasty for keratoconus.

Treatment of foveal pigment epithelial detachments with contiguous extrafoveal choroidal neovascular membranes.

BB-gun injuries to the eye

Accuracy of visible retinal emboli for the detection of cardioembolic lesions requiring anticoagulation or cardiac surgery